Neurons throughout the brain communicate using both single action potentials and discrete clusters of action potentials called spike bursts or complex spikes. Bursts consist of groups of fast Na+ spikes or spikelets, often at precise intervals, which ride atop a strong depolarizing Ca2+ spike. Given the bidirectionality of spike propagation in neurons (into axons and dendrites), spike bursts represent a discrete and powerful packaged signal: a set of high-frequency Na+ spikes for the axon and a biochemically and electrically potent Ca2+ spike for the dendrite. Not surprisingly, bursts have relevance to sensory processing, network computations, learning and memory, enhanced salience of specific signals, and induction of some forms of epilepsy. A major gap in our understanding is in how spike bursts arise in neurons and what controls their generation and properties. Using a brainstem inhibitory interneuron network (cartwheel cells) as a model system, we explore the hypotheses that a) bursts arising in the axon initial segment (AIS) transform in size, shape, and probability as they forward propagate along the axon and backpropagate into the dendrites, b) the AIS is the site for receptor-mediated modulation of bursts, c) spike bursts provide the trigger for a novel circuit-level plasticity. These ideas will be tested using patch-clamp recording combined with two-photon microscopy and uncaging, and a new voltage imaging technique. The results will aid in understanding network function and dysfunction throughout the brain. PUBLIC HEALTH RELEVANCE: This is a proposal to examine the control of electrical burst-like signaling within single neurons, and how that signaling determines the activity of neighboring neurons. The study will have impact on topics as diverse as sensory processing and drug addiction.